Mass transport properties of progesterone and estradiol in model microemulsion formulations

The purpose of these studies was to determine the extent to which drug loading influences the mass transport characteristics of poorly soluble steroids from model microemulsion formulations in vitro.

Two conditions of drug loading in the microemulsions were tested, "near saturation" and "constant loaded." Mass flux of (3)H-labelled progesterone or estradiol was measured in a side-by-side diffusion chamber from microemulsions consisting of Brij 97, Miglyol 812 and water. Pulsed gradient NMR was used to measure the diffusivities of all components. The thermodynamic activity and fraction of free drug in the formulations were measured by polymer uptake. Solute flux was calculated employing an aqueous boundary layer model.

Under near saturation loading, all microemulsion formulations showed significantly increased flux of steroids compared to the saturated aqueous solution. For both steroids flux values in the 0.5 and 1% systems were significantly lower for the 3% oil formulation, despite the observation that the 3% formulation held significantly more drug. On the other hand, for all the formulations under constant drug loading, solute flux was only moderately increased for progesterone and not at all for estradiol when compared to the saturated aqueous solution. Under both loading conditions, thermodynamic activities did not correlate to flux indicating some other factor was modulating mass transport. Effective diffusivities of the steroids in formulations as determined by NMR were significantly reduced compared to those of the monomer drug in aqueous solution. In both near-saturated and constant-loaded conditions, the calculated values for progesterone flux were markedly similar to those observed experimentally suggesting solubilization and diffusion events in the aqueous boundary layer had a strong influence on mass transport. In contrast, calculations for estradiol were less successful in modeling the observed flux values.

In systems nearly saturated with drug, the microemulsion formulation leads to a greatly enhanced rate of steady-state mass transport while in systems with drug loading far from saturation, the microemulsion formulation appears to have a minimal ability to promote mass transport. The aqueous boundary layer diffusion model was successful in fitting progesterone results but was not successful for estradiol.